Use of Sotrovimab in Pregnancy: Experiences from the COVID-19 International Drug Pregnancy Registry.

INTRODUCTION: Available data regarding the safety and efficacy of sotrovimab in pregnant patients remain limited due to their exclusion from clinical trials. METHODS: The COVID-19 International Drug Pregnancy Registry (COVID-PR) was established to gather comprehensive safety data from pregnant women who have received monoclonal antibody (mAb) or antiviral treatments for mild, moderate, or severe coronavirus disease 2019 (COVID-19) during pregnancy. Participants actively contributed self-reported data concerning their COVID-19 symptoms, in addition to sociodemographic and health-related characteristics. Obstetric, neonatal, and infant outcomes were also documented, with follow-up extending up to 12 months after childbirth. RESULTS: As of 30 November 2023, sotrovimab was administered to 39 participants enrolled in the COVID-PR. At the time of this report, 26 participants had given birth, with nine deliveries performed via cesarean section. The infants' birthweight ranged from 2381 g to 4762 g, with a mean of 3439.91 g. Twenty-five infants were born at ≥37 weeks. A total of 31 adverse events (AEs) were reported by 12 participants. The most frequently reported AE was gestational hypertension, observed in three participants. COVID-19 re-infection, fatigue, gestational diabetes, headache, and morning sickness were each reported by two participants. Of the reported AEs, eight (in five participants) were classified as serious, including four AEs (prolonged labor, pre-eclampsia, polyhydramnios, premature labor) that affected pregnancy. Seven of these eight serious AEs (SAEs) were found to be unrelated to sotrovimab, with one event (urinary retention) not assessable. A total of 44 AEs were reported in 19 delivered infants or in utero fetuses. The most common were COVID-19 (n = 6 events), ear infection (n = 5 events), neonatal dyspnea (n = 3 events), and respiratory syncytial virus infection (n = 3 events). Sixteen AEs (in 11 infants/fetuses) were classified as serious, including one report each of fetal cardiac disorder, congenital ankyloglossia, persistent right umbilical vein, and congenital hydronephrosis; the latter was considered a major congenital malformation. For all assessable SAEs, causality of sotrovimab treatment was ruled out based on lack of a temporal relationship alone or in combination with absence of a plausible mechanism. CONCLUSION: A sizable proportion of sotrovimab-treated participants in the COVID-PR had underlying medical conditions associated with an increased risk of severe COVID-19. None of the assessable SAEs were considered to be related to sotrovimab treatment.

Drug Utilization Studies in Pregnant Women for Newly Licensed Medicinal Products: A Contribution from IMI ConcePTION.

Purpose: Studies focusing on safety outcomes typically require large populations to comprehensively characterise the patient groups exposed to the medicines under investigation. However, there is often less information for subpopulations, such as pregnant or breastfeeding women, particularly when new medicines are considered. It is important to understand what information can be obtained from drug utilization studies (DUS) involving pregnant women in the early years postmarketing to provide supportive information for safety studies. The aims of this literature review are to (1) identify and review DUS for new medicines in pregnancy and breastfeeding and (2) list and summarise key information items to be reported in a DUS for new medicines in pregnancy. Methods: To identify postmarketing DUS of new prescription medicines or enantiomers in pregnancy, a systematic literature review was undertaken in PubMed and Embase between January 2015 and June 2022. In addition, the complete database of the ENCePP EU PAS Register was systematically searched to June 2022. Results: We identified 11 published DUS on new medicines in pregnancy from the ENCePP EU PAS Register and none from other sources. No studies on breastfeeding were identified. The 11 identified publications reported the medicine's use for the first 3 to 5 years after marketing approval. No reports assessed utilization in the first 3 years of approval. It was usual to issue interim reports annually (7 studies). All studies concerned conditions managed in ambulatory care (primary care and outpatient facilities) and included some primary care prescribing. Most (n = 8) only had prescribing/dispensing data available at individual level for ambulatory care; outpatient prescribing was included in three of these studies Three studies held a limited amount of in-hospital prescribing data. A DUS can confirm at an early stage whether there are sufficient exposed pregnancies in available data sources to ensure a safety study is powered to detect a difference in the prevalence of adverse pregnancy or infant outcomes or if additional data from other databases are needed. A DUS may also help address methodological considerations such as selection of comparators. DUS can be performed embedded in a DUS in the general population, in a cohort of women of childbearing age, or in a cohort of pregnant women. Conclusion: This review summarises key aspects of a DUS for new medicines in pregnancy. DUS for new medicines in pregnancy should be planned before marketing, scheduled for the first 3 to 5 years after release, with annual interim/progress reports, and reported in peer-reviewed journals. By offering detailed information on data sources, exposure timing, prevalence and location, coprescribing, comorbidities, coexposures, and demographics, a DUS will offer a firm foundation for safety studies and will help to contextualize spontaneous reporting of serious adverse events.

Call to action: Harmonization of pharmacovigilance regulations for post-marketing pregnancy and breastfeeding safety studies.

Globally, more than 200 million women become pregnant each year, most of whom receive medications despite limited information on their safe use during pregnancy. The paucity of drug safety data on pregnant and breastfeeding women stems from the routine exclusion of this population from clinical trials due to scientific, ethical, regulatory and legal concerns. Consequently, at the time of initial drug approval, there may be scant safety data to inform the drug benefit-risk balance to the mother, foetus or infant. Although momentum is growing to include this underrepresented population in clinical trials, most information on drug exposure outcomes comes from data collected in the postmarketing setting. Regulatory guidance and legislation on medication use in pregnancy and breastfeeding were reviewed globally by the TransCelerate IGR PV Pregnancy and Breastfeeding Team. The International Conference of Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) standards and Council for International Organizations of Medical Sciences guidelines served as benchmarks for national safety regulations and guidance. The landscape assessment identified a lack of harmonization of global regulations on research in pregnant and breastfeeding women and a lack of specific regulations on this topic in the majority of the territories included in the assessment. This article focuses on the ambiguities and lack of harmonization in global regulations on postmarketing pregnancy and breastfeeding safety studies. There is currently no ICH standard to guide these types of safety studies and, in most regions reviewed, there are no clear regulations or guidance on when and how to conduct them. While a challenging undertaking, greater clarity and harmonization would facilitate more timely completion of postmarketing pregnancy safety studies that would ultimately generate the critical data needed to optimize benefit-risk decisions for women who may conceive, as well as pregnant and breastfeeding women.

Regulations Governing Medicines for Maternal and Neonatal Health: A Landscape Assessment.

Limited evidence related to the safety or efficacy of medicines in pregnancy and during breastfeeding is available to inform patients and healthcare professionals. Understanding the current regulatory landscape in the clinical trial and postmarketing settings is critical to facilitate the development of applicable processes and tools for studying medicine use during pregnancy and breastfeeding and comply with health authority expectations. This review summarizes key findings from a landscape assessment of regulations, guidelines, and guidance on the use of medicines in pregnancy and breastfeeding issued by health authorities in various territories (including the Americas, Europe, Africa, and Asia Pacific) and outlines relevant initiatives undertaken by health authorities, academic institutions, industry consortia, and public-private organizations. While global pharmacovigilance legislation regarding medication use during pregnancy and breastfeeding exists and continues to evolve, the landscape assessment revealed that there is a lack of global legislative harmonization in both the clinical trial and postmarketing surveillance settings and regulatory gaps still exist in many countries/regions. Despite ongoing efforts from health authorities and public and private organizations, intensive efforts for legislation harmonization and stakeholder collaboration are required to improve the current environment of medication safety in pregnancy and breastfeeding.

Belimumab use during pregnancy: Interim results of the belimumab pregnancy registry.

BACKGROUND: Belimumab is approved for active, autoantibody-positive systemic lupus erythematosus (SLE) and lupus nephritis, but limited data exist regarding its use in pregnancy. The Belimumab Pregnancy Registry (BPR, GSK Study BEL114256; NCT01532310) was created to evaluate pregnancy and infant outcomes following belimumab exposure. METHODS: Individuals with SLE exposed to belimumab from 4 months before and/or during pregnancy can enroll into the BPR. The primary outcome is major birth defects; secondary outcomes include miscarriages, stillbirths, elective termination, pre-term birth, neonatal death, small for gestational age, and adverse infant outcomes during the first year of life. Belimumab exposure timing, concomitant medications, and other potential confounding factors are also collected. Data up to March 8, 2021, are reported descriptively. RESULTS: From an expected sample size target of 500 prospective pregnancies with a known outcome, only 55 were enrolled in the study. Among these, two pregnancy losses and 53 pregnancies with a live birth outcome were reported. Ten of the 53 live birth pregnancies resulted in a major birth defect. Ten pregnancies were enrolled after the pregnancy outcome occurred and were examined retrospectively (four live births with no defects, four miscarriages, and two elective terminations). There was no indication or pattern of birth defects associated with belimumab. CONCLUSIONS: Low recruitment numbers for the BPR and incomplete information limit the conclusions regarding belimumab exposure during pregnancy. There was no pattern or common mechanism of birth defects associated with belimumab within the BPR data.

Belimumab use during pregnancy: a summary of birth defects and pregnancy loss from belimumab clinical trials, a pregnancy registry and postmarketing reports.

OBJECTIVE: Describe available data on birth defects and pregnancy loss in women with systemic lupus erythematosus (SLE) exposed to belimumab. METHODS: Data collected from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports up to 8 March 2020 were described. Belimumab exposure timing, concomitant medications and potential confounding factors were summarised descriptively. RESULTS: Among 319 pregnancies with known outcomes (excluding elective terminations), 223 ended in live births from which birth defects were identified in 4/72 (5.6%) in belimumab-exposed pregnancies and 0/9 placebo-exposed pregnancies across 18 clinical trials, 10/46 (21.7%) belimumab-exposed pregnancies in the BPR prospective cohort (enrolled prior to pregnancy outcome) and 0/4 belimumab-exposed pregnancies in the BPR retrospective cohort (enrolled after pregnancy outcome), and 1/92 (1.1%) in belimumab-exposed pregnancies from postmarketing/spontaneous reports. There was no consistent pattern of birth defects across datasets. Out of pregnancies with known outcomes (excluding elective terminations), pregnancy loss occurred in 31.8% (35/110) of belimumab-exposed women and 43.8% (7/16) of placebo-exposed women in clinical trials; 4.2% (2/48) of women in the BPR prospective cohort and 50% (4/8) in the BPR retrospective cohort; and 31.4% (43/137) of belimumab-exposed women from postmarketing/spontaneous reports. All belimumab-exposed women in clinical trials and the BPR received concomitant medications and had confounding factors and/or missing data. CONCLUSIONS: Observations reported here add to limited data published on pregnancy outcomes following belimumab exposure. Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.

Fitness of real-world data for clinical trial data collection: Results and lessons from a HARMONY Outcomes ancillary study.

BACKGROUND: Despite the extensive use of real-world data for retrospective, observational clinical research, our understanding of how real-world data might increase the efficiency of data collection in patient-level randomized clinical trials is largely unknown. The structure of real-world data is inherently heterogeneous, with each source electronic health record and claims database different from the next. Their fitness-for-use as data sources for multisite trials in the United States has not been established. METHODS: For a subset of participants in the HARMONY Outcomes Trial, we obtained electronic health record data from recruiting sites or Medicare claims data from the Centers for Medicare & Medicaid Services. For baseline characteristics and follow-up events, we assessed the level of agreement between these real-world data and data documented in the trial database. RESULTS: Real-world data-derived demographic information tended to agree with trial-reported demographic information, although real-world data were less accurate in identifying medical history. The ability of real-world data to identify baseline medication usage differed by real-world data source, with claims data demonstrating substantially better performance than electronic health record data. The limited number of lab results in the collected electronic health record data matched closely with values in the trial database. There were not enough follow-up events in the ancillary study population to draw meaningful conclusions about the performance of real-world data for identification of events. Based on the conduct of this ancillary study, the challenges and opportunities of using real-world data within clinical trials are discussed. CONCLUSION: Based on a subset of participants from the HARMONY Outcomes Trial, our results suggest that electronic health record or claims data, as currently available, are unlikely to be a complete substitute for trial data collection of medical history or baseline lab results, but that Medicare claims were able to identify most medications. The limited size of the study population prevents us from drawing strong conclusions based on these results, and other studies are clearly needed to confirm or refute these findings.

Development and evaluation of standardized pregnancy identification and trimester distribution algorithms in U.S. IBM MarketScan® Commercial and Medicaid data.

OBJECTIVES: Creation of new algorithms to identify pregnancies in automated health care claims databases is of public health importance, as it allows us to learn more about medication use and safety in a vulnerable population. Previous algorithms were largely created using international classification of disease codes, but despite the U.S. code transition in 2015, few algorithms are available with the latest ICD-10-CM codes. METHODS: Using U.S. IBM MarketScan® Commercial Claims and Encounters and Multi-State Medicaid databases for women aged 10-64 years during 2014 and 2016, two pregnancy algorithms (ICD-9-CM and ICD-10-CM) were created using expert clinical review. The algorithms were evaluated by assessing the distribution of pregnancy outcomes (live birth and pregnancy losses) within each time-based cohort and the ability of the algorithms to identify select medication use during pregnancy. Medication exposure, demographics, comorbidities, and pregnancy outcomes were compared to published literature estimates for the two time periods. RESULTS: For the IBM MarketScan® Commercial database, the algorithms identified 687,228 pregnancies in 2014 and 444,293 in 2016. In the IBM MarketScan® Medicaid database, 389,132 pregnancies in 2014 and 406,418 in 2016 were identified. Percentages of most pregnancy outcomes identified using the algorithms were similar to national data sources; however, percentages of preterm births and pregnancy losses were not comparable. Most medication use estimates from the algorithms were similar to or higher than published estimates. CONCLUSIONS: By incorporating the latest ICD-10-CM codes, the new algorithms provide more complete estimates of medication use during pregnancy than algorithms using the outdated codes.

The safety of asthma medications during pregnancy and lactation: Clinical management and research priorities.

Asthma is one of the most common underlying diseases in women of reproductive age that can lead to potentially serious medical problems during pregnancy and lactation. A group of key stakeholders across multiple relevant disciplines was invited to take part in an effort to prioritize, strategize, and mobilize action steps to fill important gaps in knowledge regarding asthma medication safety in pregnancy and lactation. The stakeholders identified substantial gaps in the literature on the safety of asthma medications used during pregnancy and lactation and prioritized strategies to fill those gaps. Short-term action steps included linking data from existing complementary study designs (US and international claims data, single drug pregnancy registries, case-control studies, and coordinated systematic data systems). Long-term action steps included creating an asthma disease registry, incorporating the disease registry into electronic health record systems, and coordinating care across disciplines. The stakeholders also prioritized establishing new infrastructures/collaborations to perform research in pregnant and lactating women and to include patient perspectives throughout the process. To address the evidence gaps, and aid in populating product labels with data that inform clinical decision making, the consortium developed a plan to systematically obtain necessary data in the most efficient and timely manner.

A model for human and animal data integration: Weight of evidence strategy.

BACKGROUND: Integration of animal and human data to assess potential risks of the use of medications in pregnancy is important. A qualitative weight of evidence process enables all available evidence to be considered in a consistent, systematic manner. METHODS: We aim to describe the weight of evidence methodology utilized by the authors, a summary of which was presented at the 59th Annual Meeting of the Teratology Society entitled "Integration of Human and Animal Data to Inform Medication Use in Pregnant Women." The qualitative weight of evidence process evaluates data that inform on a potential relationship between an adverse pregnancy outcome and a medication exposure. An interdisciplinary panel evaluates all available human and animal data related to the question of interest. Study quality assessments of both human and animal data are incorporated. The evaluation assesses gaps in the data from the following areas: (a) strength, (b) specificity, (c) consistency, (d) dose response relationship, (e) methodological considerations, and (f) biological plausibility for the potential association of interest. RESULTS: The panel integrates all the information to arrive at an assessment of the evidence and provides recommendations, which may include obtaining more specific information. We provide examples of how the authors apply this process at a pharmaceutical company for evaluation of potential postmarketing safety issues regarding medications and pregnancy outcomes. CONCLUSIONS: This weight of evidence method improves the ability to integrate published literature and other data sources to assess the potential risks of medication use in pregnant women and inform future drug safety studies.

Perinatal Outcomes Associated with Maternal Asthma and Its Severity and Control During Pregnancy.

BACKGROUND: Estimates of the effects of maternal asthma on pregnancy outcomes are inconsistent across studies, possibly because of differences in exposure definition. OBJECTIVE: To evaluate the risk of adverse perinatal outcomes associated with maternal asthma diagnosis, severity, and control in a large, nationally representative cohort. METHODS: This study was conducted within the IBM Health MarketScan Commercial Claims and Encounters Database (2011-2015) and the Medicaid Analytic eXtract database (2000-2014). Asthma was identified by diagnosis and treatment codes, severity was based on medications dispensed, and control was based on short-acting ß-agonist dispensations and exacerbations. We estimated the relative risks (RRs) of stillbirth, spontaneous abortion, preterm birth, small for gestational age (SGA), neonatal intensive care unit (NICU) admission, and congenital malformations, comparing pregnancies with differing asthma disease status. RESULTS: We identified 29,882 pregnancies complicated by asthma in the MarketScan database and 160,638 in the Medicaid Analytic eXtract database. We observed no consistent associations between asthma diagnosis, severity, or control, and stillbirth, abortions, or malformations. However, we observed increased risks of prematurity, SGA, and NICU admission among women with asthma compared with those without asthma. Compared with women with well-controlled asthma, women with poor control late in pregnancy had an increased risk of preterm birth (relative risk, 1.39; 95% CI, 1.32-1.46) and NICU admission (relative risk, 1.26; 95% CI, 1.17-1.35). More severe asthma was associated with SGA (relative risk, 1.18; 95% CI, 1.07-1.30). CONCLUSIONS: We did not observe an increased risk of pregnancy losses or malformations among women with asthma. However, we found an association between asthma severity and SGA, and between exacerbations late in pregnancy and preterm delivery and NICU admission.

Poorly Controlled Asthma During Pregnancy Remains Common in the United States.

BACKGROUND: Asthma is among the most common preexisting medical conditions in pregnancy. Uncontrolled asthma may increase the risk of adverse pregnancy outcomes. OBJECTIVES: To describe the prevalence, severity, and control of asthma during pregnancy in the United States. METHODS: We identified 2 cohorts of pregnancies ending in a live birth within 2 large US health care claims databases: the Truven Health MarketScan Commercial Claims and Encounters Database (MarketScan, private insurance) for the period 2011 to 2015 and the nationwide Medicaid Analytic eXtract (MAX, public insurance) for the period 2000 to 2013. We defined asthma prevalence, severity, and control on the basis of International Classification of Diseases, 9th Revision diagnoses and asthma-related treatments. Severe asthma was defined as dispensing of 1 or more medium/high-dose inhaled corticosteroid plus additional therapy within the 12 months preceding delivery. Poor control was defined as having at least 1 of the following: 1 or more exacerbation (asthma-related hospitalization or emergency room visit, or a course of oral corticosteroids) or 5 or more filled prescriptions for short-acting ß-agonists between the last menstrual period and delivery. RESULTS: Among 604,420 pregnant women in MarketScan and 2,071,359 in MAX, 20,104 (3.3%) and 120,745 (5.8%) had asthma, respectively. Among pregnant women with asthma, 19.0% and 18.8% had severe asthma and 16.5% and 28.0% had poorly controlled asthma in MarketScan and MAX, respectively. Many women with poorly controlled asthma during pregnancy were not dispensed a long-term controller (38.4% in MarketScan and 43.3% in MAX). Within both cohorts, women with poor control were more often smokers and obese, had more comorbidities, and used more concomitant nonasthma medications. CONCLUSIONS: Poorly controlled asthma is more frequent among publicly versus privately insured pregnancies in the United States. Dispensing of long-term controller medications during pregnancy remains low, even for symptomatic patients.

Chronic airway obstruction in a population-based adult asthma cohort: Prevalence, incidence and prognostic factors.

BACKGROUND: Asthma and COPD may overlap (ACO) but information about incidence and risk factors are lacking. This study aimed to estimate prevalence, incidence and risk factors of chronic airway obstruction (CAO) in a population-based adult asthma cohort. METHODS: During 1986-2001 a large population-based asthma cohort was identified (n = 2055, 19-72y). Subsamples have participated in clinical follow-ups during the subsequent years. The entire cohort was invited to a clinical follow-up including interview, spirometry, and blood sampling in 2012-2014 when n = 983 subjects performed adequate spirometry. CAO was defined as post-bronchodilator FEV1/FVC<0.7. RESULTS: At study entry, asthmatics with prevalent CAO (11.4%) reported more respiratory symptoms, asthma medication use, and ischemic heart disease than asthmatics without CAO (asthma only). Subjects who developed CAO during follow-up (17.6%; incidence rate of 16/1000/year) had a more rapid FEV1 decline and higher levels of neutrophils than asthma only. Smoking, older age and male sex were independently associated with increased risk for both prevalent and incident CAO, while obesity had a protective effect. CONCLUSIONS: In this prospective adult asthma cohort, the majority did not develop CAO. Smoking, older age and male sex were risk factors for prevalent and incident CAO, similar to risk factors described for COPD in the general population.

Use of clinical characteristics to predict spirometric classification of obstructive lung disease.

Background: There is no consensus on how to define patients with symptoms of asthma and chronic obstructive pulmonary disease (COPD). A diagnosis of asthma-COPD overlap (ACO) syndrome has been proposed, but its value is debated. This study (GSK Study 201703 [NCT02302417]) investigated the ability of statistical modeling approaches to define distinct disease groups in patients with obstructive lung disease (OLD) using medical history and spirometric data. Methods: Patients aged ≥18 years with diagnoses of asthma and/or COPD were categorized into three groups: 1) asthma (nonobstructive; reversible), 2) ACO (obstructive; reversible), and 3) COPD (obstructive; nonreversible). Obstruction was defined as a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity <0.7, and reversibility as a post-albuterol increase in FEV1 ≥200 mL and ≥12%. A primary model (PM), based on patients' responses to a health care practitioner-administered questionnaire, was developed using multinomial logistic regression modeling. Other multivariate statistical analysis models for identifying asthma and COPD as distinct entities were developed and assessed using receiver operating characteristic (ROC) analysis. Partial least squares discriminant analysis (PLS-DA) assessed the degree of overlap between groups. Results: The PM predicted spirometric classifications with modest sensitivity. Other analysis models performed with high discrimination (area under the ROC curve: asthma model, 0.94; COPD model, 0.87). PLS-DA identified distinct phenotypic groups corresponding to asthma and COPD. Conclusion: Within the OLD spectrum, patients with asthma or COPD can be identified as two distinct groups with a high degree of precision. Patients outside these classifications do not constitute a homogeneous group.

Burden of asthma and COPD overlap (ACO) in Taiwan: a nationwide population-based study.

BACKGROUND: Patients with symptoms of both asthma and chronic obstructive pulmonary disease (COPD) may be classified with the term asthma-COPD overlap (ACO). ACO is of considerable interest as it is currently poorly characterised and has been associated with worse health outcomes and higher healthcare costs compared with COPD or asthma alone. Patients with ACO in Asia remain poorly described, and there is limited information regarding their resource utilisation compared with patients with asthma or COPD only. This study investigated the characteristics, disease burden and medical resource utilisation of patients with ACO in Taiwan. METHODS: This was a retrospective cohort study of patients identified from National Health Insurance (NHI) claims data in Taiwan in 2009-2011. Patients were classified into incident ACO, COPD or asthma cohorts according to International Classification of Disease, ninth revision, clinical modification codes in claims. Eligible patients were ≥40 years of age with 12 months' continuous enrolment in the NHI programme pre- and post-index date (date of the first relevant medical claim). RESULTS: Patients with ACO (N = 22,328) and COPD (N = 69,648) were older and more likely to be male than those with asthma (N = 50,293). Patients with ACO had more comorbidities and exacerbations, with higher medication use: short-acting ß2-agonist prescriptions ranged from 30.4% of patients (asthma cohort) to 43.6% (ACO cohort), and inhaled corticosteroid/long-acting ß2-agonist combination prescriptions ranged from 11.1% (COPD cohort) to 35.0% (ACO cohort) in the 12 months following index. Patients with ACO generally had the highest medication costs of any cohort (long-acting muscarinic antagonist costs ranged from $227/patient [asthma cohort] to $349/patient [ACO cohort]); they also experienced more respiratory-related hospital visits than patients with asthma or COPD (mean outpatient/inpatient visits per patient post-index: 9.1/1.9 [ACO cohort] vs 5.7/1.4 [asthma cohort] and 6.4/1.7 [COPD cohort]). CONCLUSIONS: Patients with ACO in Taiwan experience a greater disease burden with greater healthcare resource utilisation, and higher costs, than patients with asthma or COPD alone.

Asthma and Chronic Obstructive Pulmonary Disease Overlap: The Effect of Definitions on Measures of Burden.

Background: Although the overlap between asthma and COPD has been recognized for years this overlap has only recently been given a name, asthma-COPD overlap syndrome (ACOS), and better defined. Different definitions of the component diseases can affect prevalence and outcome measures of ACOS. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) from 2007-2012 to determine the population estimates of ACOS in U.S. adults using 2 different definitions of ACOS (ACOS1= self-reported COPD and current asthma; ACOS2 = spirometric-confirmed COPD [pre-bronchodilator FEV1/FVC < 70%] and current asthma) and to describe variation in other factors, such as lung function impairment and health care utilization, by ACOS definitions. Results: Among U.S. adults aged 20 and older, 1.6% had ACOS1, and 1.9% had ACOS2. Both case definitions were similar with regard to symptoms and impairment of lung function. ACOS1 individuals were more likely to have one or more overnight hospital stays relative to those with neither asthma nor COPD, (odds ratio [OR] 3.4, 95% confidence interval [CI] 2.5, 4.6) than ACOS2 (OR 1.6, 95% CI 0.9, 2.9). Conclusions: Different definitions of ACOS in population-based studies affect both estimates of disease prevalence and outcomes related to the disease. These definitions need to be carefully considered in the design of epidemiologic studies and clinical trials.

Disease Burden of Patients with Asthma/COPD Overlap in a US Claims Database: Impact of ICD-9 Coding-based Definitions.

The inclusion of an asthma/chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) population in the 2015 Global Initiative for Chronic Obstructive Lung Disease strategic documents has raised questions about the profile of these patients in clinical practice, as they are mostly excluded from asthma and COPD clinical trials. We estimated the disease burden, co-morbidities, and respiratory treatments of patients with asthma/COPD overlap, utilizing the Truven MarketScan commercial and Medicare databases. Patients with ≥1 COPD or chronic obstructive asthma diagnostic code were identified between January 1, 2008, and December 31, 2011. The asthma/COPD overlap group was defined and stratified based upon type and frequency of asthma diagnostic code (chronic obstructive asthma only, COPD and chronic obstructive asthma, and COPD and ≥1 asthma code). 1,488,613 patients were identified; of these, 1,171,626 were diagnosed with COPD alone and 316,987 with asthma/COPD overlap. Patients with asthma and COPD had higher disease burden indicators and inhaled corticosteroid/long-acting beta-agonist use compared with COPD alone. This trend was consistent for all definitions of asthma/COPD overlap. Patients with obstructive asthma and COPD tended to be older, with greater disease burden compared with other definitions; this population may represent a more severe form of asthma/COPD overlap. Disease burden and treatment also varied based on the codes defining asthma/COPD overlap, indicating possible phenotypic differences. More clinical insight and detailed phenotyping is needed to determine the reasons for coding variation in asthma/COPD overlap, with implications for further research to address unmet needs.

Can Assessment of Disease Burden Prior to Changes in Initial COPD Maintenance Treatment Provide Insight into Remaining Unmet Needs? A Retrospective Database Study in UK Primary Care.

This retrospective cohort study aimed to assess treatment patterns over 24 months amongst patients with chronic obstructive pulmonary disease (COPD), initiating a new COPD maintenance treatment, and to understand clinical indicators of treatment change. Patients included in the study initiated a long-acting ß2-agonist (LABA), a long-acting muscarinic antagonist (LAMA), or a combination of LABA and an inhaled corticosteroid (ICS/LABA) between January 1, 2009, and November 30, 2013, as recorded in the United Kingdom Clinical Practice Research Datalink (UK CPRD). Treatment modifications (switching or adding maintenance treatments) over 24 months were assessed, and patient characteristics, disease burden, medication and healthcare resource use during the 30 days before treatment modification were evaluated. The cohort comprised 17,258 patients [LABA (8%), LAMA (39%) and ICS/LABA (54%)] with similar age, body mass index and dyspnoea distribution. LABA users were more likely than LAMA users to add a maintenance therapy. Distinct patterns of treatment augmentations were noted, whereby LABA users typically received dual therapy before moving to triple therapy, while LAMA users moved to triple therapy by directly adding an ICS/LABA. Exacerbation events immediately prior to treatment change were not frequently recorded; however, the need for rescue short-acting medication and assessment of dyspnoea in the 30 days prior to the treatment change suggest that dyspnoea is a remaining unmet need driving therapy change.

A Swedish Population-based Study of Adverse Birth Outcomes among Pregnant Women Treated with Buprenorphine or Methadone: Preliminary Findings.

BACKGROUND: Untreated opioid dependence in pregnant women is associated with adverse birth outcomes. Buprenorphine and methadone are options for opioid agonist medication-assisted treatment during pregnancy. OBJECTIVE: The aim of this study was to describe adverse birth outcomes observed with buprenorphine or methadone treatment compared to the general population in Sweden. METHODS: Pregnant women and their corresponding births during 2005-2011 were identified in the Swedish Medical Birth Register. Data on stillbirth, neonatal/infant death, mode of delivery, gestational age at birth, Apgar score, growth outcomes, neonatal abstinence syndrome, and congenital malformations were examined. Frequencies were compared using two-sided Fisher's exact tests. Unadjusted estimates of birth outcomes for women treated with buprenorphine or methadone were compared to the registered general population. RESULTS: A total of 746,257 pregnancies among 538,178 unique women resulted in 746,485 live births. Among the 194 women treated with buprenorphine (N = 176) or methadone (N = 52), no stillbirths or neonatal/infant deaths occurred. Neonatal abstinence syndrome developed in 23.3% and 38.5% of infants born to mothers treated with buprenorphine and methadone, respectively. The frequency of the selected adverse birth outcomes assessed in women treated with buprenorphine as compared to the general population was not significantly different. However, a significantly higher frequency of preterm birth and congenital malformations was observed in women treated with methadone as compared to the general population. Compared with the general population, methadone-treated women were significantly older than buprenorphine-treated women, and both treatment groups began prenatal care later, were more likely to smoke cigarettes, and did not cohabitate with the baby's father. CONCLUSIONS: An increased frequency of the selected adverse birth outcomes was not observed with buprenorphine treatment during pregnancy. Twofold increased frequency of preterm birth [2.21 (1.11, 4,41)] and congenital malformations [2.05 (1.08, 3.87)] was observed in the methadone group, which may be partly explained by older average maternal age and differences in other measured and unmeasured confounders.